Alcohol has deleterious effects on the bone of adult and developing animals. Previous work in our lab has shown that chronic alcohol intake during pregnancy in the rat reduces birth weight and retards fetal skeletal development. In addition we have shown that alcohol consumption has adverse effects on bone of the pregnant female herself. Importantly, our studies show that alcohol impairs the ability of the pregnant dam and fetus to regulate their Ca metabolism. Fetal life and pregnancy are both periods in which bone is vulnerable to alcohol's adverse effects due to the growth and development of the fetal skeleton and the increased Ca required by the dam to support its mineralization. In the present proposal, we will expand our studies on the pregnant female and the fetus to investigate further the effects of alcohol on Ca regulation and bone.
Our Specific Aims are to determine: 1) the mechanisms underlying the impaired Ca regulation of pregnant rats consuming alcohol; and 2) if the effect of alcohol on fetal growth and skeletal development results from the inability of the dam to regulate her blood iCa levels.
Specific Aim 1 will test the hypotheses that alcohol interferes with the ability of the pregnant rat to increase serum levels of PTH and 1,25(OH)2D in response to a decrease in blood iCa levels, resulting in a) a lack of increase in Ca reabsorption by the kidney, b) a failure to increase intestinal Ca absorption, and c) an inability to mobilize adequate Ca from bone.
Specific Aim 2 will test the hypotheses that the decrease in maternal blood iCa levels retards fetal growth and skeletal development by causing a decrease in fetal blood iCa levels, which may a) inhibit bone formation directly, or b) trigger a compensatory response by the fetus, such as an increase in secretion of parathyroid hormone related peptide (PTHrP) or parathyroid hormone (PTH), which may in turn inhibit bone formation. The proposed studies will begin to elucidate mechanisms underlying the effects of alcohol on bone during 2 periods in which bone mass is vulnerable to perturbation: pregnancy and fetal development. Alcohol-induced perturbations in bone mass may have significant implications for the development of osteoporosis, which is a major health care issue today.
